Placenta-derived CXCL1 is associated with fetal renal dysplasia upon gestational cadmium treatment.

Congenital anomalies of the kidney and urinary tract are the leading cause of chronic kidney disease in children. Cadmium (Cd is a developmental toxicant that acts primarily by impairing placental function. However, the underlying placenta-origin injury mechanisms of gestational Cd-induced fetal renal dysplasia have not been fully elucidated. Here, we established a mouse model by administering pregnant CD-1 mice a single intraperitoneal injection of cadmium chloride solution (0, 2.25, and 4.50 mg/kg) on gestational day 8. We demonstrated that gestational Cd treatment induced placental senescence and inhibited fetal renal proliferation. Based on the integration of mouse placental transcriptomic data with a senescence-associated secretory phenotype (SASP) database of human-mouse orthologous secretory proteins, we identified CXCL1 as a key SASP factor mediating Cd-induced fetal renal dysplasia. Additionally, mouse intervention experiments demonstrated that resveratrol supplementation effectively reversed both placental senescence and renal dysplasia. In cellular experiments, treatment with CXCL1 inhibited the proliferation of human embryonic kidney (HEK293T) cells. Furthermore, in human studies, CXCL1 expression was also increased in senescent placentae, and elevated neonatal serum CXCL1 levels were negatively correlated with renal function. Overall, these findings suggest that placenta-derived CXCL1 is associated with fetal renal dysplasia upon gestational Cd treatment, which provides a central mechanism for fetal-derived diseases.